The proposed studies investigate the basis for individual differences in smoking behavior using a drug discrimination paradigm in both rats and humans. During years 01 and 02 of the candidate's training, differences in the discriminative stimulus properties of nicotine will be characterized in rats bred for differences in muscarinic sensitivity. Each rat's capability for in-vivo desensitization will be determined by testing their ability to detect a specific nicotine training dose at various times after an initial challenge dose. Generalization and antagonism studies with various pharmacologic agents will be performed. The candidate will continue active involvement with the animal laboratory as she proceeds on to perform clinical research in humans in years 03, 04, and 05. Initially the focus will be to establish the methodology , for nicotine discrimination experimentation in humans. Identifying the cues for nicotine detection and looking at individual differences in sensitivity amongst different levels of smokers are additional research aims. Future experiments to look at differences in human desensitization, and to test pharmacologic generalization and antagonism will parallel the rat studies.